Cluster Headache Pathophysiology—A Disorder of Network Excitability?

Abstract

Patients’ accounts of cluster headache attacks, ictal restlessness, and electrophysiological studies suggest that the pathophysiology involves Aδ-fibre nociceptors and the network processing their input. Continuous activity of the trigeminal autonomic reflex throughout the in-bout period results in central sensitization of these networks in many patients. It is likely that several factors force circadian rhythmicity upon the disease. In addition to sensitization, circadian changes in pain perception and autonomic innervation might influence the excitability of the trigeminal cervical complex. Summation of several factors influencing pain perception might render neurons vulnerable to spontaneous depolarization, particularly at the beginning of rapid drops of the pain threshold (“summation headache”). In light of studies suggesting an impairment of short-term synaptic plasticity in CH patients, we suggest that the physiologic basis of CH attacks might be network overactivity—similarly to epileptic seizures. Case reports documenting cluster-like attacks support the idea of distinct factors being transiently able to induce attacks and being relevant in the pathophysiology of the disorder. A sustained and recurring proneness to attacks likely requires changes in the activity of other structures among which the hypothalamus is the most probable candidate.

What Cluster Headache Patients Would Like Their Relatives to Know: Results from a Qualitative Study

“…Many patients describe the pain as localized and sharp [10] and some even liken it to a knife stuck in the head [11]. Several authors thus concluded that this pain feels "escapable" [12] and hypothesized that it is irrelevant for the human brain whether a knife is stuck in the head or if it only feels like there is one: in either case, the affected person engages in an involuntary defence reaction that may feel and manifest like aggression [12,13]. Hence, not seeing another person may prevent directing aggression against them.…”

History of cluster headache

“…Animal experiments suggest a reduction of central sensitisation that may help prevent attacks. 82,[84][85][86] The insights that vasoconstrictive agents could end migraine attacks, and that stimulation of serotonin receptors induced vasoconstriction, led to the development of a specific 5-hydroxytyramin agonist. The first one became known as sumatriptan.…”

“…Still, the hypothalamus remains a likely candidate for the ‘ primum movens ’. 84 It is left for future research to explore its role in detail.…”

“…Animal experiments suggest a reduction of central sensitisation that may help prevent attacks. 82,84 –86…”

Circadian functional changes of pain‐processing brainstem nuclei and implications for cluster headache: A 7 Tesla imaging study

“…Cluster headache (CH) attacks do not appear randomly throughout the day but happen most often in the hours after midnight and least frequently around noon. 1,2 Although this type of pain is not nociceptive, it seems to implicate the activation of nociceptors-most likely A-delta fibers. 3 Nociceptors signal tissue damage and distention to the brain, which may interpret the input as pain; however, their activation is not equally likely to result in pain at every time of the day.…”